tbuckley/cabot-search huggingface dataset:
NIMG-20. ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES
Authors: Jan-Michael Werner, Philipp Lohmann, Christoph Kabbasch, Michael Wollring, Caroline Tscherpel, Gabriele Stoffels, Roland Goldbrunner, Karl-Josef Langen, Gereon Fink, Norbert Galldiks
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Currently, data on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI parameters for the evaluation of response to regorafenib in glioma patients remain scarce. METHODS Twenty patients (age range, 30-72 years) with recurrent CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) were treated according to the REGOMA trial. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, various apparent diffusion coefficients (ADC) parameters were obtained from diffusion-weighted MRI. Thresholds derived from FET PET and ADC parameters were defined using ROC analyses to predict an overall survival (OS) of ≥6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). After two cycles of regorafenib, a reduction of mean TBR values by ≥10% predicted significantly longer OS (9.9 vs. 5.3 months; P=0.023). Additionally, absolute mean TBR values ≤2.0 at follow-up were prognostic and associated with a significantly longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or were prognostic (all P &amp;gt;0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P&amp;lt; 0.001; HR, 0.005). CONCLUSION In contrast to MRI metrics, FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication.
MODL-36. EX VIVO GSC CULTURES RETAIN PATIENT-UNIQUE HALLMARK GENE EXPRESSIONS AND PREDICT PATIENT RESPONSE TO TMZ MORE SPECIFICALLY THAN MGMT PROMOTER STATUS
Authors: Ioannis Ntafoulis, Anne Kleijn, Jie Ju, Kevin Jimenez-Cowell, Federica Fabro, Michelle Klein, Romain Tching Chi Yen, Rutger Balvers, Trisha Kers, Johan Kros, Sean Lawler, Andreas Kremer, Yunlei Li, Andrew Stubbs, Martin van den Bent, Clemens Dirven, Sieger Leenstra, Martine Lamfers
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). METHODS DNA and RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Drug response readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. RESULTS Tumor DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. Patient-specific hallmark gene expression levels were retained in vitro. Functional screening for TMZ sensitivity yielded three response categories (responders, intermediates and non-responders) which significantly correlated with patient survival, therewith providing a more specific response prediction than the binary MGMT marker. Transcriptome analysis of GSCs and parental tissues identified 121 genes related to TMZ sensitivity and overall survival, of which 21, including MGMT, could be validated in external datasets. CONCLUSION GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma patients.
DNAR-11. NUCLEAR POTASSIUM GOVERNS NUCLEAR ENVELOPE INTEGRITY AND GENOMIC STRUCTURE IN MEDULLOBLASTOMA
Authors: Jade Chan, Chi-chung Hui, Xi Huang
Journal: Neuro-Oncology (2023)

Abstract Potassium is the most abundant intracellular cation with crucial functions such as regulating cell proliferation, migration, and differentiation. Potassium flux across cellular membranes is controlled by potassium channels. While the role of cytosolic potassium has been researched for many decades, very little is known about the modulation or significance of potassium in the cell nucleus. Here, we identify potassium channel subunit KCNG1 as a novel regulator of nuclear potassium in medulloblastoma (MB), the most common malignant pediatric brain tumour. Using genetically encoded Förster resonance energy transfer (FRET)-based potassium sensors, we show that KCNG1 regulates nuclear potassium level independently of cytosolic potassium level. KCNG1 knockdown alters the genomic architecture of MB cells by stabilizing G-quadruplex (G4) DNA, inducing DNA damage, and reducing nuclear envelope-associated heterochromatin. Ultimately, KCNG1 deficiency results in nuclear swelling, thereby compromising nuclear envelope integrity and inducing DNA spillage into the cytosol to activate the pro-inflammatory cGAS/STING pathway. Genetic knockdown of KCNG1 mitigates tumour growth and prolongs the survival of mice bearing MB of distinct subgroups. Altogether, our findings reveal that nuclear potassium regulates genomic structure and nuclear envelope integrity and demonstrate that targeting a nuclear potassium channel can be leveraged to activate immunogenic signalling in MB.
EXTH-25. <i>IN VIVO</i> TWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL
Authors: Nico Teske, Nayad N Kutlu, Julika J Herold, Laura Dengler, Constantin Eberle, Elene Nikolaishvili, Philipp Karschnia, Jens Blobner, Katharina Müller, Sigrid Langer, Vincenz Buschinger, Linda Warmuth, Dirk H Busch, Veit Buchholz, Niklas Thon, Joerg-Christian Tonn, Tobias Feuchtinger, Louisa von Baumgarten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed. METHODS We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing B7-H3 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. B7-H3-directed CAR T-cells were injected into the adjacent brain parenchyma. RESULTS Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against B7-H3 are currently ongoing. CONCLUSIONS We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.
STEM-10. SOX2 POSITIVE, PRESUMED TUMOR INVASION MEASURED WELL BEYOND CONTRAST ENHANCEMENT AND FLAIR HYPERINTENSITY IN BOTH TREATED AND UNTREATED GLIOBLASTOMA PATIENTS ASSESSED AT AUTOPSY
Authors: Margaret Stebbins, Samuel Bobholz, Savannah Duenweg, Allison Lowman, Michael Flatley, Biprojit Nath, Fitzgerald Kyereme, Aleksandra Winiarz, Jennifer Connelly, Dylan Coss, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract In the treatment of glioblastoma (GBM), MRI is used to determine location and extent of cancer. It is poorly understood how far tumor invasion may exist outside of contrast enhancement (CE) and FLAIR hyperintensity (FL). This study identifies presumed non-enhancing tumor invasion using SOX2 staining on tissue collected at autopsy, which may highlight invading glioma cells. Three patients with primary GBM were included for this study. Patient 1 (P1) with an overall survival (OS) of 148 days received no treatment following sub-total resection. Patient 2 (P2) (OS = 1601) and patient 3 (P3) (OS = 629 days) underwent the clinical standard of care treatment including chemo-radiation and bevacizumab at recurrence. At autopsy, brains were sliced axially to match patients’ last MRI scan. Samples were obtained including regions suspicious of tumor and regions appearing normal. SOX2 positive cells were identified visually on digitized autopsy histology. Samples were visually matched to the patient’s last T1C and FLAIR MRI acquisition prior to death. Approximate distance from CE and FL from SOX2 positive cells was measured digitally, limited to the same MRI slice (2D assessment). For P1 who received no treatment, SOX2 positive cells were identified 3.9cm from CE and 4.1cm from FL within the same hemisphere as the primary tumor, and 2.1cm and 2.3cm within the opposite hemisphere, respectively. For P2 and (P3), SOX2 positive cells were identified approximately 4.4cm (5.2 cm) from CE and 4.0cm (2.0cm) from FL within the same hemisphere as primary tumor, and 4.7cm (4.4cm) from CE and 4.1 cm (4.7cm) from FL within the opposite hemisphere. This study uses SOX2 to identify presumed GBM cells well beyond clinically identified regions of tumor, on T1C and FLAIR imaging. Additional research is necessary to determine SOX2 sensitivity and specificity for identifying GBM cells outside regions with readily identifiable GBM characteristics.
EPID-16. A MULTI-CENTER, PROGRESSION-FREE SURVIVAL ANALYSIS IN IDH-MUTANT GLIOMAS WITH <i>CDKN2A</i> DELETION: IMPLICATIONS FOR PROGNOSIS AND CLINICAL TRIAL DESIGN
Authors: Julie Miller, Annie Hsieh, Amin Nohman, David Reuss, Ilker Eyuepoglu, Daniel Cahil, Christine Jungk, Tareq Juratli
Journal: Neuro-Oncology (2023)

Abstract Homozygous deletion of CDKN2A is an important predictor of poor prognosis in patients with IDH-mutant gliomas. The updated 2021 WHO classification now recognizes this alteration as sufficient for the designation of an astrocytoma, IDH-mutant, WHO Grade 4, which otherwise requires histological observation of necrosis or microvascular proliferation. While overall survival patterns associated with CDKN2A deletion have been well-described, we sought to characterize progression-free survival (PFS) in this patient population. Across three institutions (Massachusetts General Hospital, Boston; University Hospital Heidelberg, Heidelberg; TU Dresden, Dresden), we identified 48 patients with IDH-mutant gliomas in which CDKN2A deletion was detected at the time of diagnosis, followed for a median of 15.2 years. The average age of the cohort is 35 years, with 60% of the patients identified as male. Most patient received immediate treatment after surgery, with 81% of the cohort undergoing radiation therapy and 73% receiving chemotherapy. Based on RANO criteria, the median progression-free survival of this patient population is 2.8 years (95% CI 1.4 – 3.3 years) and median overall survival is 4.3 years (95% CI 2.1 – 6.6 years). A positive T2/FLAIR mismatch sign or lack of contrast enhancement on MRI at the time of diagnosis are both associated with improved PFS in univariate regression analysis. For comparison, we identified a control cohort of 51 patients with astrocytoma, IDH-mutant, grade 4 without CDKN2A deletion from MGH, achieving grade 4 by histologic criteria. Demographics were similar to the CDKN2A-deleted cohort, with median age (37 years) and percentage of male patients (60%). Notably, however, PFS for the grade 4, CDKN2A-intact, IDH-mutant glioma comparison group is estimated at 5.9 years (95% CI 3.3 – 7.9 years). Overall, these data reinforce the accelerated disease course associated with deletion of CDKN2A in IDH-mutant gliomas, providing an important reference for clinical trial design.
RADT-41. PREDICTION OF TREATMENT OUTCOME IN GAMMA KNIFE RADIOSURGERY OF BENIGN MENINGIOMAS
Authors: Hye Jeong Yang, Tae Hoon Kim, Youngchan Seo, Hyun-Tai Chung
Journal: Neuro-Oncology (2023)

Abstract Objective This study aimed to assess the predictability of machine learning (ML) ensemble models for the success of Gamma Knife radiosurgery (GKRS) on non-skull base benign meningiomas. METHODS A total of 331 non-skull base benign meningiomas treated primarily with GKRS between 1997 and 2015 were retrospectively analyzed. When a tumor remained not larger than 125% of the initial volume at the last imaging follow-up and no significant change in the high signal intensity area around the tumor, it was classified as 'treatment success (TS).' Univariate correlation and multivariate logistic regression analyses were performed to identify statistically significant prognostic factors. Four ensemble algorithms were trained to predict the outcome of GKRS. The importance of features related to TS was analyzed. RESULTS The median MR imaging follow-up period was 8.6 years. The tumor control and signal change rates were 91.5% and 16.3%, respectively, and the TS rate was 77.6%. The conventional multivariate logistic regression model showed 83.7% accuracy and 37.8% specificity. The ML models had accuracies between 78.0% and 82.2% and specificities between 30.3% and 80.7%, and they were similar to those of conventional logistic regression analyses. The smaller brain volume absorbed more than 14 Gy, and the absence of signal change before GKRS was a favorable prognostic factor for TS in all models. The bagging algorithm with selected features showed the best specificity of 80.7% and the most significant AUC of 0.723. CONCLUSION A bagging ensemble algorithm with selected features had better specificity with similar accuracy than conventional multivariate logistic regression in predicting GKRS outcomes for non-skull base meningiomas.
CTNI-04. PHASE I STUDY OF RADIATION THERAPY (RT) FOLLOWED BY INTRATHECAL (IT) TRASTUZUMAB/PERTUZUMAB IN THE MANAGEMENT OF HER2+ BREAST LEPTOMENINGEAL DISEASE (LMD)
Authors: Kamran Ahmed, Priya Kumthekar, Yolanda Pina, Youngchul Kim, Michelle DeJesus, Brittany Evernden, Daniel Oliver, Michael A Vogelbaum, Nam Tran, James Liu, Arnold Etame, Avan Armaghani, Ricardo Costa, Aixa Soyano, Kimberley Lee, John Arrington, Marilin Rosa, Hatem Soliman, Hsiang-Hsuan Michael Yu, Hyo Han, Peter Forsyth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IT trastuzumab is used in the management of HER2+ breast LMD. The monoclonal antibody pertuzumab is used with trastuzumab in the management of metastatic and localized HER2+ breast cancer. METHODS The study is a multi-institutional, phase I/II trial of RT followed by IT trastuzumab/pertuzumab. HER2+ LMD patients with a life expectancy &amp;gt;8 weeks were eligible. Treatment was initiated with RT, whole brain and/or focal brain/spine RT followed by IT trastuzumab/pertuzumab. The dose of IT trastuzumab was fixed at 80 mg with a dose escalation of IT pertuzumab. An mTPI-2 design was used to determine the recommended phase II dose (RP2D). Each cycle was 4 weeks with 2x/week treatment in cycle 1, weekly in cycle 2, and every two weeks thereafter. Clinical trial information: NCT04588545. RESULTS A total of 9 patients were enrolled. Median age was 51 (range: 34-63). Seven patients (78%) were hormone receptor (HR)-/HER2+ and two were HR+/HER2+. Four dose cohorts were treated 10, 20, 40, each with one patient and 80 mg pertuzumab with six patients. Study therapy was well tolerated with no dose limiting toxicities identified. Toxicities at least partially attributable to study therapy included fatigue [grade 1 (n = 2); grade 2 (n = 1)], grade 1 extremity pain (n = 1), and grade 1 headaches (n = 1). Two patients were noted to have infected Ommaya reservoirs after which one patient resumed treatment while one patient stopped therapy after noting stable LMD for approximately 24 months. Median survival has not been reached with a 12 month OS of 86%. Best leptomeningeal response has been a partial response in 4 patients (44%) and stable disease in 5 patients (56%). Six patients continue study therapy currently. CONCLUSIONS Study therapy was well tolerated with a pertuzumab RP2D of 80 mg. Preliminary efficacy appears encouraging and continues to be assessed in the phase II portion.
RADT-48. RADIATION MYELOPATHY AFTER STANDARD DOSE RADIATION: POTENTIAL RADIATION SENSITIZING EFFECTS OF SYSTEMIC THERAPY
Authors: Allison Hazy, Inga Grills, Mohammed Ogaily, Michael Stender, Lisa R Rogers
Journal: Neuro-Oncology (2023)

Abstract Radiation myelopathy is an uncommon adverse effect of spinal irradiation. It is especially rare following conventional palliative fractionation regimens for vertebral metastasis. We present two cases of delayed thoracic radiation myelopathy in patients with breast cancer. In both cases, palliative radiation of 30 Gy in ten fractions was administered to thoracic spinal metastases. Neither patient received concurrent systemic therapy. One began trastuzumab emtansine nine days after finishing radiation and the other started palbociclib three months afterwards, which was switched to capecitabine at disease progression. Each patient developed progressive leg weakness and numbness, ten months following radiation and eleven months following radiation (four weeks following capecitabine), respectively. MRI showed edema and focal contrast enhancement within the radiation field in each. Both were treated with high-dose corticosteroid, vitamin E, and pentoxifylline. Neither patient returned to their neurologic baseline and remain with significant deficits, requiring assistance with ambulation. Serial MRIs revealed eventual reduction in cord enhancement and edema, followed by cord atrophy in one case. The cumulative radiation dose of 30 Gy is typically within the safety tolerance of the spinal cord, so it is speculative if post-radiation systemic therapy played a role in the development of myelopathy. The timing is particularly convincing in the patient who developed symptoms within four weeks of starting capecitabine. These cases are similar to recently reported instances of radiation myelopathy after standard dose spinal radiation followed by chemotherapy or immunotherapy. Recognition of the potential radiation sensitizing effects of systemic therapy should lead clinicians to consider radiation myelopathy early if spinal cord symptoms develop and to consider the timing of initiation of potential sensitizing drugs when spinal radiation has been given.
CNSC-37. THE ASSOCIATION BETWEEN THE NUMBER OF HIGH-DOSE METHOTREXATE CYCLES AND LONGER REMISSION PERIODS IN PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE REVIEW
Authors: Joshua Nahm, Mousumi Sinha, Eva Highberg Schumann, Mia Vu, Cornelius Ware, Sigmund Hsu, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2023)

Abstract Representing 3-4% of newly diagnosed central nervous system tumors, primary central nervous system lymphomas (PCNSL) are rare, extra-nodal non-Hodgkin lymphomas with an overall survival (OS) of 91.9 months. Though patients can achieve a complete response (CR) after first-line therapy, PCNSL typically recurs within two years. Standard treatment involves high-dose methotrexate (HD-MTX)-based polychemotherapy, but the ideal number of HD-MTX cycles that achieves and maintains a CR is unclear. To address this question, we conducted a retrospective review of PCNSL patients. The primary outcome was median OS. Secondary outcomes included the OS of recurrent PCNSL patients (rOS), number of HD-MTX cycles before the first recurrence or CR, and adverse events (AE). Survival analysis was performed using the Kaplan-Meier estimate. Forty-one patients (23 males; median age: 66) were identified. The median OS is 114 months (95% CI 44.9, NA). Twenty-nine patients achieved CR after first-line therapy with a median of five cycles. Eleven patients experienced PCNSL recurrence (rPCNSL), with five patients previously achieving a CR. The median rOS before the first recurrence was 60.4 months (95% CI 6.3, NA). The median number of cycles of HD-MTX before recurrence was three cycles, and the cumulative total of HD-MTX was five cycles. Among the 24 patients without recurrence and with CR, the median OS was not reached, but the median number of HD-MTX cycles before CR was six cycles and cumulatively was six cycles. Complete results of AEs will be updated at the meeting, but they currently include grade III hypokalemia (45.8%), grade III anemia (45.8%), and grade III acute kidney injury (25.0%). Despite the limitations of a retrospective review, our findings suggest that a higher number of HD-MTX cycles is associated with prolonged duration of remission. Future studies are warranted to determine an ideal number of HD-MTX to maintain remission state in PCNSL patients.